Compensatory ion transport buffers daily protein rhythms to regulate osmotic balance and cellular physiology
- Creators
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Stangherlin, Alessandra
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Watson, Joseph L.
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Wong, David C. S.
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Barbiero, Silvia
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Zeng, Aiwei
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Seinkmane, Estere
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Chew, Sew Peak
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Beale, Andrew D.
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Hayter, Edward A.
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Guna, Alina
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Inglis, Alison J.
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Putker, Marrit
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Bartolami, Eline
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Matile, Stefan
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Lequeux, Nicolas
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Pons, Thomas
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Day, Jason
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van Ooijen, Gerben
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Voorhees, Rebecca M.
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Bechtold, David A.
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Derivery, Emmanuel
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Edgar, Rachel S.
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Newham, Peter
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O'Neill, John S.
Abstract
Between 6–20% of the cellular proteome is under circadian control and tunes mammalian cell function with daily environmental cycles. For cell viability, and to maintain volume within narrow limits, the daily variation in osmotic potential exerted by changes in the soluble proteome must be counterbalanced. The mechanisms and consequences of this osmotic compensation have not been investigated before. In cultured cells and in tissue we find that compensation involves electroneutral active transport of Na⁺, K⁺, and Cl⁻ through differential activity of SLC12A family cotransporters. In cardiomyocytes ex vivo and in vivo, compensatory ion fluxes confer daily variation in electrical activity. Perturbation of soluble protein abundance has commensurate effects on ion composition and cellular function across the circadian cycle. Thus, circadian regulation of the proteome impacts ion homeostasis with substantial consequences for the physiology of electrically active cells such as cardiomyocytes.
Additional Information
© Crown 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Received 26 May 2020; Accepted 04 August 2021; Published 15 October 2021. We thank Alex Harmer, Helen Causton, and past and present O'Neill lab members for valuable discussion and contribution, particularly Priya Crosby and Ned Hoyle, visual aids, and the biological services group for assistance with animal work and husbandry. Funding: E.D. was supported by the Medical Research Council (MC_UP_1201/13) and the Human Frontier Science Program (CDA00034/2017-C); RSE by a Wellcome Trust Sir Henry Dale Fellowship (208790/Z/17/Z). This work was supported by the AstraZeneca Blue Skies Initiative and the Medical Research Council (MC_UP_1201/4). Data availability: The data supporting the findings of this study are available in the main article and supplementary files or from the corresponding author upon reasonable request. Source data are provided with this paper as Source Data File. The original mass spectra and search engine files used in this study have been deposited in the public proteomics repository MassIVE as MSV000087673 [https://massive.ucsd.edu/ProteoSAFe/dataset.jsp?accession=MSV000087673]. Source data are provided with this paper. Code availability: The codes used detection, tracking, and analysis of quantum dots are available for download through GitHub (https://github.com/deriverylab/Stangherlin2021). Author Contributions: J.S.O., P.N., R.S.E., and A.S. conceived the idea and wrote the manuscript. E.B and S.M. synthesized the cell penetrating poly(disulfide)s, T.P. and N.P. synthesized quantum dots. A.S., J.W., D.W., S.B., A.Z., E.S., S.P.C., A.B., E.H., A.G, A. I., M.P., J.D., R.V., D.B., E.D., and R.S.E. performed experiments and analysis, G.v.O. made pivotal intellectual contributions. P.N. holds shares in AstraZeneca. The other authors declare no competing interests. Peer review information: Nature Communications thanks Annie Curtis, Olivier Staub, and other, anonymous, reviewers for their contributions to the peer review of this work. Peer review reports are available.Errata
Stangherlin, A., Watson, J.L., Wong, D.C.S. et al. Publisher Correction: Compensatory ion transport buffers daily protein rhythms to regulate osmotic balance and cellular physiology. Nat Commun 12, 6988 (2021). https://doi.org/10.1038/s41467-021-26725-7Attached Files
Published - s41467-021-25942-4.pdf
Submitted - 2020.05.28.118398v1.full.pdf
Supplemental Material - 41467_2021_25942_MOESM1_ESM.pdf
Supplemental Material - 41467_2021_25942_MOESM2_ESM.pdf
Supplemental Material - 41467_2021_25942_MOESM3_ESM.mp4
Supplemental Material - 41467_2021_25942_MOESM4_ESM.mp4
Supplemental Material - 41467_2021_25942_MOESM5_ESM.docx
Supplemental Material - 41467_2021_25942_MOESM6_ESM.pdf
Supplemental Material - 41467_2021_25942_MOESM7_ESM.zip
Supplemental Material - 41467_2021_26725_MOESM1_ESM.pdf
Erratum - s41467-021-26725-7.pdf
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Additional details
- PMCID
- PMC8520019
- Eprint ID
- 103524
- Resolver ID
- CaltechAUTHORS:20200528-134326798
- Medical Research Council (UK)
- MC_UP_1201/13
- Human Frontier Science Program
- CDA00034/2017-C
- Wellcome Trust
- 208790/Z/17/Z
- AstraZeneca Blue Skies Initiative
- Medical Research Council (UK)
- MC_UP_1201/4
- Created
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2020-05-28Created from EPrint's datestamp field
- Updated
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2021-12-03Created from EPrint's last_modified field
- Caltech groups
- Division of Biology and Biological Engineering (BBE)